Postbiotics as a Therapeutic Target in Cognitive Impairment: Exploring into Molecular Pathways and Neuroprotective Effects.

Cognitive impairment (CI) refers to impairment of cognitive domains that comprise memory, attention, language, and processing speed that exceed normal age-related changes and interfere with daily functions. Its pathophysiology includes neuronal dysfunction of synaptic activity, cerebral hypoperfusion, microglial inflammatory response, oxidative stress, mitochondrial dysregulation, impairment of the blood-brain barrier (BBB), and lipopolysaccharide (LPS). These interconnected mechanisms promote neuroinflammatory responses, impair neuronal connectivity, and gut-brain axis (GBA) balance, thereby contributing to the development and progression of CI. Postbiotics are non-viable microbial cells or structural components with therapeutic potential without live colonisation. They promote synaptic plasticity, reduce oxidative stress and neuroinflammation, enhance BBB integrity, improve mitochondrial activity, and regulate neurotransmitter levels, including serotonin, dopamine, and γ-aminobutyric acid (GABA). Postbiotics can be utilised in CI for their ability to generate bioactive metabolites that enhance gut-brain axis communication, immune modulation, and neuronal and BBB activity. Emerging preclinical evidence indicates that postbiotics modulate key pathological processes, including synaptic plasticity, oxidative stress, neuroinflammation, and BBB integrity; however, the majority of these findings are derived from in vitro and animal models, with limited clinical validation. This review aims to provide a systematic evaluation of the role of postbiotics in the prevention and management of CI across different neurological and metabolic disorders, and to summarise the available preclinical findings with potential therapeutic implications and future directions.